10th NTES Symposium
Review
Neurodegenerative diseases and therapeutic strategies using iron chelators

https://doi.org/10.1016/j.jtemb.2014.12.012Get rights and content

Abstract

This review will summarise the current state of our knowledge concerning the involvement of iron in various neurological diseases and the potential of therapy with iron chelators to retard the progression of the disease. We first discuss briefly the role of metal ions in brain function before outlining the way by which transition metal ions, such as iron and copper, can initiate neurodegeneration through the generation of reactive oxygen and nitrogen species. This results in protein misfolding, amyloid production and formation of insoluble protein aggregates which are contained within inclusion bodies. This will activate microglia leading to neuroinflammation. Neuroinflammation plays an important role in the progression of the neurodegenerative diseases, with activated microglia releasing pro-inflammatory cytokines leading to cellular cell loss. The evidence for metal involvement in Parkinson's and Alzheimer's disease as well as Friedreich's ataxia and multiple sclerosis will be presented. Preliminary results from trials of iron chelation therapy in these neurodegenerative diseases will be reviewed.

Introduction

The human brain gives us the power to speak, imagine and problem solve as well as the ability to perform a number of tasks, which include the control of body temperature, blood pressure, heart rate and breathing, accept information from various senses, such as visual, auditory and smell, as well as allowing one to think, dream, reason and experience emotions. However, it is difficult to imagine how mental entities such as thoughts and emotions could be implemented by physical entities such as neurons, glial cells and synapses or by any other type of mechanism. For these reasons, the way in which the brain can perform such functions remains one of the greatest scientific challenges of the 21st century. Recently the Human Brain Project has been launched by the European Commission [1], which should go a long way to improving our understanding of brain function in health and disease, as well as the changes which occur with ageing. It has as its goal to lay the technical foundations for a new model of ICT-based brain research, driving integration between data and knowledge from different disciplines, and catalysing a community effort to achieve a new understanding of the brain, new treatments for brain disease and new brain-like computing technologies. Thanks to the progress of modern medicine, and to improved living standards, the life expectancy of the human race continues to increase steadily, unlike other mammals. However, the downside is that as our population ages, the risk of contracting one of a number of neurodegenerative diseases also increases. The most common of these are dementias, characterised by decline in cognitive faculties and the occurrence of behavioural abnormalities which interfere with the capacity of the afflicted individual to carry out normal daily activities. It most often affects elderly individuals and the most common is Alzheimer's disease (AD). Dementia prevalence increases with age; in the USA whereas 5.0% of those aged 71–79 years are affected, this climbs to 37.4% of those aged 90 and older [2].

In this review, we outline some of the mechanisms underlying neurodegenerative diseases which involve the essential metal iron and discuss some of the preliminary results which have used the therapeutic strategy of chelation to remove potentially toxic iron from the brain.

Section snippets

The importance of metals in the brain

A number of important biological functions in the brain require metal ions such as potassium, sodium, calcium and zinc together with the redox-active iron and copper [3]. For example, the fast transmission of electrical impulses between neurons and along their axons to muscles and endocrine tissues, the maintenance of ionic gradients and the synthesis of neurotransmitters require these metal ions. The opening and closing of gated sodium and potassium channels to generate electrochemical

Metal-based neurodegeneration

Over the last decade, it has become more and more widely accepted that inflammation, associated with dysfunction of metal ion homeostasis (Fe, Cu, Zn) resulting in concomitant oxidative stress, are key factors in a large number of neurodegenerative diseases [10], [11]. Support comes from the observation that AD, PD and many other neurodegenerative diseases are characterised by increased levels of these metal ions in specific regions of the brain.

The ‘metal-based neurodegeneration hypothesis’ is

Iron chelation and neurodegeneration

The possible therapeutic use of iron chelators to remove the excess amounts of iron from specific brain regions which occurs in different neurodegenerative diseases has received considerable attention over the past few years. The iron chelator should essentially be able to penetrate cellular membranes as well as the blood–brain barrier, target the region of iron accumulation without depleting transferrin bound iron from the plasma, and be able to remove the chelatable iron from the site of

Parkinson's disease

Changes in brain iron homeostasis occur in Parkinson's disease patients, with elevated levels of iron, in the form of H-ferritin and neuromelanin, occurring in the substantia nigra, SN. Furthermore in the early stages of PD, no changes in iron content of other brain regions have been noted. Neuroinflammation and neurodegeneration occur in the SN, probably due to the presence of Lewy bodies and precipitated α-synuclein, activating microglia, which will accumulate iron as a result of up

Alzheimer's disease (AD)

High levels of zinc, copper and iron are present in the insoluble amyloid plaques in post-mortem AD brains, such that disequilibrium of these essential trace elements possibly plays a role in the misfolding process which occurs with amyloid, Aβ, aggregation. The toxicity of any excessive amounts of iron is exemplified by the fact that increased amounts of iron will influence furin activity (which is important for the activation of secretases) such that low levels of furin (induced by high

Friedreich's ataxia (FRDA)

Friedreich's ataxia is the most common of the hereditary ataxias, the occurrence being one case in 50,000 individuals in the Caucasian population, and is caused by triplet repeat extensions in the frataxin gene. The first symptoms usually develop during childhood or puberty with a life expectancy between 40 and 50 years. The most common mutation in the frataxin gene is an expanded GAA trinucleotide repeat in intron 1 of the frataxin gene which occurs in approximately 96% of frataxin patients.

Multiple sclerosis (MS)

MRI and histological studies have shown global alterations in iron levels in the brains of MS patients in deep grey matter structures, which are associated with increased disability and grey matter atrophy. In addition, increases in the iron stored by macrophages and microglia are also evident which may indicate that a pathogenic process is occurring. Iron overload is also evident in macrophages which will promote a pro-inflammatory M1 activation state (see below). Such increases in iron have

Neuroinflammation

Neuroinflammation plays an important role in the pathogenesis of many of the neurodegenerative diseases. Such inflammation is induced possibly by the presence of misfolded proteins which act as a catalyst for the activation and sustained activity of glial cells. Glial cells, i.e. microglia, astrocytes and oligodendrocytes have important roles in the brain. Microglia play an important role in maintaining normal CNS function, as well as continually searching for alterations in brain homeostasis

Parkinson's disease (PD)

In the PD brain proliferation of microglia is observed early in the disease process and was reported to remain relatively static and unrelated to the extent of striatal degeneration and disease severity (reviewed in [37]). However the advanced dopaminergic degeneration in symptomatic PD has been associated with an overproduction of cytotoxic cytokines, which could indicate that microglia are polarised to a mainly M1 phenotype in advanced PD disease [38]. Therefore multiple phenotypes may exist

Alzheimer's disease (AD)

Alzheimer's disease (AD) is characterised by a classical neuropathology: intraneuronal accumulations of hyperphosphorylated microtuble-associated protein tau known as neurofibrillary tangles (NFTs), and extracellular deposition of amyloid β-peptide (Aβ) known as amyloid or senile plaques. Age-dependent neuro-inflammatory changes may play a significant role in this process, where microglia switch from an M2 to M1 phenotype. It was originally hypothesised (the amyloid cascade hypothesis) that the

Multiple sclerosis

MS is an auto-immune disorder of the CNS characterised by inflammatory destruction of the myelin sheath of the long axons of motor neurons, the oligodendrocytes being the principal target of the inflammatory attack. Focal lymphocytic infiltration occurs which leads to damage to the myelin and axons. The hallmark sign is the formation of the sclerotic plaque which represents the end stage of a process involving inflammation, demyelination and remyelination, oligodendrocyte depletion and

Concluding remarks

Considering the importance of metal ions in the normal functions of the human brain, it is not surprising that dysregulation of metal homeostasis should have harmful effects on brain function. A growing body of data supports the view that the redox-active metals iron and copper can generate oxidative stress and inflammation, leading to protein misfolding and aggregation associated with many neurodegenerative diseases. There is an increasing evidence that disruption of iron regulation plays a

Conflict of interest

There are no conflicts of interest by any of the authors.

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